The goal of these studies is to elucidate the developmental biology of the human fetal adrenal gland. Our underlying hypothesis is that the unique structure, rate of growth and steroidogenic function of the human fetal adrenal is the net effect of ACTH secreted from the fetal pituitary and a cohort of growth factors expressed by the fetal adrenal of which insulin-like growth factor-II (IGF-II) is a major component. Based upon our preliminary findings and those of others, our specific aims are to determine: the mechanisms by which the fetal adrenals grows; the functions of the various cortical zones; the mechanism by which ACTH regulates growth and function; and the role of IGF-II in fetal growth and function. Understanding the growth and differentiation of the fetal adrenal gland is to cardinal importance because of 1) the pivotal role adrenal corticosteroids play in early enzyme induction, the coordinate development of independent organ systems necessary or intrauterine homeostasis and extrauterine survival (e.g. feta lung maturation, deposition of glycogen in the fetal liver, and induction of enzymes in the fetal brain, thyroid, gastrointestinal tract and retina), the response to intrauterine and perinatal stress; 2) the pathologic alteration of growth that occurs in congenital adrenal hyperplasia, which we hypothesize is the result of the overexpresion of locally produced growth factors stimulated by excess ACTH; 3) the atavistic reversion to a fetal mode of function in adult adrenal neoplasms; and 4) the insights into more general aspects of human organ growth that this understanding will provide. We will utilize cell culture and molecular biological techniques, as well as two newly develop;ed in vivo models (fetal adrenal tissue grafted under the kidney capsule of the athymic mouse and endogenous stimulation of the hypothalamic-pituitary-adrenal axis of the fetal rhesus monkey) to address our specific aims concerning the developmental biology of the human fetal adrenal gland. The proposed studies are to investigate specific aspects of growth and differentiation in the human fetal adrenal with the aim of determining the mechanism by which these processes are regulated. Ultimately, these adrenal with the aim of determining the mechanisms by which these process are regulated. Ultimately, these studies should contribute to knowledge of the role of the fetal adrenal in intrauterine development and homeostasis, the regulation of normal and altered human pregnancy, as well as greater understanding of the mechanisms of trophic hormone action on target tissue.